Acetazolamide, Nifedipine and Phosphodiesterase Inhibitors: Rationale for Their Utilization as Adjunctive Countermeasures in the Treatment of Coronavirus Disease 2019 (COVID-19).

Abstract

Effective treatments for Coronavirus Disease 2019 (COVID-19) outbreak are urgently needed. While anti-viral approaches and vaccines are being considered immediate countermeasures are unavailable. The aim of this article is to outline a perspective on the pathophysiology of COVID-19 in the context of the currently available clinical data published in the literature. This article appreciates clinical data published on COVID-19 in the context of another respiratory illness - high altitude pulmonary edema (HAPE). Both conditions have significant similarities that portend pathophysiologic trajectories. Following this potential treatment options emerge.Both COVID-19 and HAPE exhibit a decreased ratio of arterial oxygen partial pressure to fractional inspired oxygen with concomitant hypoxia and tachypnea. There also appears to be a tendency for low carbon dioxide levels in both as well. Radiologic findings of ground glass opacities are present in up to 86% of patients with COVID-19 in addition to patchy infiltrates. Patients with HAPE also exhibit patchy infiltrates throughout the pulmonary fields, often in an asymmetric pattern and CT findings reveal increased lung markings and ground glass-like changes as well. Widespread ground-glass opacities are most commonly a manifestation of hydrostatic pulmonary edema. Similarly, elevated fibrinogen levels in both conditions are likely an epiphenomenon of edema formation rather than coagulation activation. Autopsy results of a COVID-19 fatality revealed bilateral diffuse alveolar damage associated with pulmonary edema, pro-inflammatory concentrates, and indications of early-phase acute respiratory distress syndrome (ARDS). HAPE itself is initially caused by an increase in pulmonary capillary pressure and induces altered alveolar-capillary permeability via high pulmonary artery hydrostatic pressures that lead to a protein-rich and mildly hemorrhagic edema. It appears that COVID-19 and HAPE both discretely converge on ARDS. In light of this, a countermeasure that has been shown to be effective in the analogous condition of HAPE is Acetazolamide. Acetazolamide has a myriad of effects on different organ systems, potently reduces hypoxic pulmonary vasoconstriction, improves minute ventilation and expired vital capacity. Other therapeutics to consider that are also directed towards decreased pulmonary pressure include Nifedipine and Phosphodiesterase inhibitors.This review describes COVID-19 in parallel to HAPE. Deranged respiratory parameters that are present in both conditions are highlighted. The utilization of medications found to be effective in HAPE, for the treatment of COVID-19, is proposed. Given the medical emergency of a growing contagion and the thousands of lives at stake, expedient attempts to improve survival are needed. Acetazolamide, Nifedipine and Phosphodiesterase inhibitors may be potential countermeasures.